During the later phases, they selectively increase the signal intensity of the liver via hepatocyte uptake , thus aiding in the detection of small tumors. This is dependent on the degree of differentiation of the tumor, as well-differentiated hepatocellular carcinoma may take up the contrast and become less conspicuous. However, these agents are best utilized for detection of metastases. In addition, because of biliary excretion during the delayed phase, the biliary ducts can be mapped well using T1-weighted images T1-weighted MR cholangiography. Although they are now available in Europe, neither of these agents is yet approved for clinical use in the United States.
At present, these agents are widely used for the detection and characterization of various neoplastic, infectious, and ischemic processes in the brain and for the depiction of vascular anatomy Figure 1; MRA. Using MR perfusion imaging for the detection of acute cerebral ischemia helps in the decision-making regarding the use of thrombolytic therapy. In body imaging, these agents are specifically used for the detection of various tumors in the liver and pancreas. They are also used also for the characterization of the tumors based on enhancement characteristics, such as peripheral nodular and centripetal enhancement for hemangioma Figure 2 , rim enhancement for metastases, and preferential arterial-phase enhancement for hepatoma Figure 3.
Various studies have shown that MR contrast agents improve the sensitivity, specificity, and accuracy of MR procedures.
As previously mentioned, these contrast agents are targeted to specific organs or tissues so there is a significant positive or negative enhancement of those organs or tissues after the administration of these contrast agents. The liver-specific MR contrast agents are targeted toward hepatocytes or reticuloendothelial cells and provide either positive or negative enhancement after intravenous IV administration Table 3. Hepatocyte-specific contrast agents include mangafodipir trisodium and two gadolinium chelates: The reticuloendothelial-cell-specific agents are small particulate iron oxides-ferumoxides and ferucarbotran.
It has chemical similarity to vitamin B 6 , and, because of this, it is specifically taken up by hepatocytes. However, evidence exists that metabolic products of this compound are also responsible for selective uptake into the liver, pancreas, and cardiac muscle. The adverse events commonly reported include facial flushing and a hot sensation. The prolonged imaging window makes this agent a good choice for imaging the liver.
The signal intensity of normal hepatic parenchyma is increased, providing high lesion-to-liver contrast. This aids in the detection of small liver lesions. Therefore, this agent is best used for the detection of metastases Figure 4. During the later phases, this contrast agent is excreted into bile Figure 4 and provides excellent biliary ductal detail and aids in the diagnosis of various biliary pathologies, such as biliary obstruction and bile leaks.
Gadolinium chelates-- Two gadolinium chelates exhibit liver specificity because of their selective uptake by hepatocytes through a carrier-mediated transport across the cell membrane. These agents are excreted into the bile unaltered and are ultimately excreted via both urine and feces. After IV administration, these agents have an initial intravascular phase similar to other gadolinium chelates, but during the later phase, they accumulate in the liver parenchyma and increase the signal intensity of the liver. Thus, the lesion-to-liver contrast is increased, and these agents aid in the detection of small liver lesions.
Similar to that obtained with any other gadolinium chelate, the initial intravascular phase helps in the characterization of the liver lesions Figure 5.
In addition, in similar fashion to mangafodipir trisodium, these agents also provide excellent biliary ductal detail during the delayed phase. Ferumoxides-- This reticuloendothelial-specific superparamagnetic iron oxide SPIO agent provides negative enhancement of the liver after IV infusion. Ferumoxides are made up of a central iron oxide particle-Fe 2 O 3 , a superparamagnetic compound surrounded by a dextran coating. Though the central core of iron oxide measures only 3 to 5 nm, the actual size in the circulation is approximately 50 nm because of hydration of the dextran coating.
Because of this effect, these agents cause a loss of signal at the site of accumulation-ie, the normal liver turns dark. These agents need to be infused slowly over a period of 30 minutes to avoid cardiovascular effects and lumbar pain.
After the intracellular uptake, SPIOs are metabolized in the lysosomes into a soluble, nonsuperparamagnetic form of iron that becomes part of the normal iron pool eg, ferritin, hemoglobin, etc. It is important to note that lesions that contain reticuloendothelial cells, such as focal nodular hyperplasia, may become isointense to normal liver because of a decreased lesion-to-liver contrast ratio.
Therefore, on some occasions, a questionable focal nodular hyperplasia may be confirmed on ferumoxide-enhanced MR Figure 6. However, because of the relative inconsistency in the amount of reticuloendothelial cells in focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma, such clinical use is not routinely recommended. In addition, well-differentiated hepatocellular carcinoma may also contain reticuloendothelial cells, resulting in decreased lesion conspicuity. The detection of metastases, however, is improved with this agent.
Like mangafodipir trisodium, this agent also provides a long imaging window after IV infusion, thus facilitating high-spatial-resolution thin-section imaging. Ferucarbotran-- Like ferumoxides, ferucarbotran contains a polycrystalline iron oxide core Fe 2 O 3 and Fe 2 O 4 and a carbodextran coating. Unlike ferumoxides, this agent can be safely injected rapidly in a bolus fashion, and the incidence of cardiovascular adverse events and back pain are significantly less. Although this agent was found to cause significant T1 shortening of blood, its use for MRA was found to be suboptimal.
These agents circulate in the intravascular space for a longer period of time than other agents and cause a significant reduction in the T1 relaxation time of circulating blood; thus, these agents are best suited for MRA. However, simultaneous imaging of multiple regions of interest eg, the thoracoabdominal aorta and peripheral limb arteries is not possible. In addition, low-field MR imaging does not allow for rapid scanning of the vascular tree during the short intravascular phase of gadolinium chelates.
Thus, blood-pool agents would be desirable for high-quality MRA. Several such agents are in development, but none is currently approved for clinical use Table 4. Various approaches have been taken to make the contrast agents strictly intravascular or to provide a longer intravascular phase of distribution. One of the approaches is to modify the currently available contrast agents in such a way that they become protein-bound during the intravascular phase and do not diffuse into extravascular space. Both of these agents reversibly bind to circulating albumin and remain in the intravascular space for longer periods of time.
Initial clinical studies showed good visualization of the coronary arteries during the first pass and excellent MRA of other arteries, even in delayed phases. Such a lesion shows intense and homogeneous contrast uptake in the arterial-phase, with decay in the portal and delayed phases, presenting greater hepatobiliary contrast uptake than the adjacent parenchyma, suggesting FNH as the first diagnostic hypothesis.
Considering that the presence of intralesional fat in NFH is rare, the patient will be maintained under imaging follow-up. The lesions in segments VII and VIII arrows are similar, with marked hypersignal on T2-weighted, hyposignal on T1-weighted sequence, and nodular, peripheral and discontinuous uptake in the arterial phase, a characteristic of hemangiomas. In cirrhosis, the hepatobiliary contrast uptake by the nodules depends on their differentiation stage and on the presence of functioning hepatocytes. Low-grade regenerative and dysplastic nodules present preferentially portal vascularization, contain functioning hepatocytes and, like the surrounding parenchyma, show hepatobiliary contrast uptake.
High-degree dysplastic nodules lose the portal vascularization and start gaining abnormal arterial vascularization. Thus, high-grade dysplastic nodules tend to be hypovascular in the arterial and portal phases, but may also become hypervascular in the arterial phase in cases where the abnormal arterial vascularization is more developed. High-grade dysplastic nodules contain functioning hepatocytes and also demonstrate hepatobiliary contrast uptake in the same way as the surrounding parenchyma Figure 5.
Hepatobiliary contrast uptake by HCC also depends on its differentiation stage. Well-differentiated HCCs contain functioning hepatocytes and might show hepatobiliary contrast uptake. On the other hand, poorly-differentiated or undifferentiated hepatocarcinomas do not contain functioning hepatocytes and do not show hepatobiliary contrast uptake, remaining hypointense in relation to the surrounding parenchyma 2 , 10 , 17 - 19 Figure 6.
Small nodules are observed adjacent to the gallbladder, with hyposignal on T2-weighted sequence, without expression on the other sequences and on the conventional dynamic study, but with hepatobiliary contrast uptake, leading to the diagnosis of regenerative nodules. Well-differentiated HCCs show hepatobiliary contrast uptake, requiring imaging follow-up.
Two liver nodules are seen in the segment VIII arrows as well as a larger nodule, in the segment VI arrowheads , all of them contrast-enhanced in the arterial-phase, washout in the delayed-phase, and without uptake in the hepatobiliary-phase, characterizing HCCs. Poorly differentiated or undifferentiated HCCs do not contain functioning hepatocytes so hepatobiliary contrast uptake is not observed. The different enhancement patterns depend on the histological grade of the HCCs and may be explained by the membrane transporters expression.
Hepatobiliary contrast uptake by HCCs depends on the tumor differentiation stage and on the amount of functioning hepatocytes 2 , 4. The diagnostic performance of MRI in the detection of HCCs of all sizes increases with the utilization of hepatobiliary contrast agents 1 , However, in cases of advanced cirrhosis, the contrast uptake by the liver parenchyma may be compromised by decreased hepatocytes function, which would result in reduction of the method's accuracy to detect HCCs 4 , The differentiation between HCC and perfusion alterations may also represent a diagnostic challenge.
Perfusional alterations present a signal similar to the one of the remainder hepatic tissue during the portal and hepatobiliary phases, while most HCCs, except the well-differentiated ones, present hyposignal in the hepatobiliary phase The hepatobiliary phase may also be useful in the post-chemoembolization or post-radiofrequency ablation follow-up, considering that inflammatory reactions show hepatobiliary contrast uptake and residual HCC tends to not present contrast uptake Hepatobiliary contrast increases the method's sensitivity to detect liver metastasis, particularly the small-sized ones.
Metastases do not contain functioning hepatocytes or biliary ducts, and do not show contrast uptake during the hepatobiliary phase.
Questions and answers re NSF and Gadolinium. The avascular lesion arrowhead is secondary to post-treatment alteration. J Magn Reson Imaging. Initially, the T1-weigthed sequences in-phase, out-ofphase and with fat saturation are performed. Surg Clin North Am. Conspicuity of hepatocellular nodular lesions in cirrhotic livers at ferumoxides-enhanced MR imaging:
As a result, the healthy hepatic tissue remains hyperintense and the metastasis, hypointense, which facilitates its detection 1 , 2. The utilization of such contrast agents increases the index of detection of hypo- and hypervascular metastases Figure 7. Additionally, hepatobiliary contrast agents contribute to the diagnosis of small, benign focal lesions frequently found in patients with neoplasias, particularly FNH Figure 8.
Like in cirrhosis, perfusional alterations in patients with metastasis show contrast uptake in the hepatobiliary phase, differently from metastases 1. Hypovascular metastases with diffusion restriction. In the hepatobiliary-phase, the liver parenchyma shows contrast uptake and becomes hyperintense. The metastatic implants that do not contain hepatocytes become hypointense.
Note the capacity of hepatobiliary contrast to detect very small lesions which cannot be visualized on the other sequences. Two hypervascular lesions arrows are seen with intermediate signal intensity on T1- and T2- weighted sequences, showing contrast uptake in the hepatobiliary-phase. Such lesions present functioning hepatocytes, suggesting FNHs as the main diagnostic hypothesis and ruling out the possibility of metastatic implants. The avascular lesion arrowhead is secondary to post-treatment alteration. The imaging evaluation of the biliary system has been approached by a series of publications in the Brazilian radiological literature 24 - The biliary excretion of hepatobiliary contrast agents allows for the anatomical and functional characterization of intra- and extrahepatic biliary tract.
Such contrast agents shortens the T1 relaxation time of the bile and allows for the performance of a high-resolution T1-weighted cholangiography 4.
The previous knowledge of the biliary anatomy and its variations becomes increasingly important in the preoperative planning, considering the complexity of the hepatic anatomy as well as of the more refined surgical techniques, which reduces the occurrence of postoperative complications 4. Also, hepatobiliary contrast-enhanced cholangiography allows for the accurate detection of postoperative complications such as biliary fistulas and bilomas which present progressive fill-in during the hepatobiliary phase.
In the postoperative follow-up, inadvertent ductal ligation can also be easily recognized in the hepatobiliary phase as an abrupt interruption of the biliary tract 4 , 5. Other applications of hepatobiliary contrast agents include the evaluation of the biliary flow dynamics, the study of partial or complete biliary duct obstructions, and the localization of the stenosis site.
The hepatobiliary contrast may contribute to the diagnosis of cholecystitis as the gallbladder is not filled by the contrast medium, differently from its habitual behavior with other contrast agents. The diagnosis of sphincter of Oddi dysfunction can be based on the finding of absent or delayed passage of the hepatobiliary contrast thru the ampulla of Vater. Hepatobiliary contrast allows for the differentiation between biliary lesions and extrabiliary cysts, since it delineates the biliary tract, demonstrating the communication of biliary cystic lesions with the bile ducts, and extrabiliary cystic lesions that do not communicate with bile ducts, such as pseudocysts, duodenal diverticula and duodenal duplication cysts 5.
Several studies are evaluating the relation between the degree of hepatic fibrosis in patients with cirrhosis As well as the hepatobiliary contrast enhancement with the objective of reducing the necessity of biopsies currently considered a gold standard. Hepatocytes are responsible for the uptake and excretion of the hepatobiliary contrast medium, so their integrity is essential for the enhancement of the parenchyma in the hepatobiliary phase. In cirrhosis, hepatocytes are progressively replaced by fibrotic tissue, so that the more advanced the fibrosis, the smaller the hepatic parenchyma enhancement in the hepatobiliary phase.
Additionally, as compared with healthy livers, cirrhotic livers present later enhancement peak and slower washout 32 - Further potential hepatobiliary contrast applications include the evaluation of the functional hepatic reserve before partial hepatectomy; evaluation of live donor's hepatic function as well as evaluation of early liver failure after transplant 4. In summary, hepatobiliary contrast increases the MRI accuracy and reduces the number of cases of undefined liver lesions. Imaging findings in the hepatobiliary findings should be always analyzed in the clinical context, considering the lesion signal characteristics on anatomical sequences.
The utilization of hepatobiliary contrast agents may reduce the necessity of invasive diagnostic procedures as well as of further investigation with other imaging methods, and imaging follow-up, reducing costs and the anxiety of both patients and medical team. Further potential hepatobiliary contrast applications include evaluation of the functional hepatic reserve before partial hepatectomy; evaluation of live donor's hepatic function as well as evaluation of early liver failure after transplant.
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